Lysosomal storage diseases(LSDs) result from deficiencies of lysosomal enzymes leading to accumulation of precursor products. The stored material eventually leads to diffuse tissue disease and premature death. Mucopolysaccharidosis VII(MPS VII) is a representative LSD characterized by absent or severely decreased levels of B-glucuronidase, with both CNS and systemic involvement. Gene transfer strategies are being investigated as a therapy to provide for a long-lasting, endogenous source of beta-glucuronidase. Preliminary data obtained with recombinant adeno-associated viruses types 4 and 5(AAV4 and AAV5) reporter viruses suggest that AAV4 or AAV5 could efficiently mediate beta-glucuronidase gene transfer to brain. As such, we propose experiments to better understand these novel vectors and to investigate their ability to correct LSD in brain. These experiments are to answer the following questions: SPECIFIC AIM 1: Can AAV5-beta-glucuronidase correct lysosomal storage diseases in the CNS of the MPSVII mouse? SPECIFIC AIM 2: Is there a polarity to AAV4-mediated ependymal cell transduction? SPECIFIC AIM 3: Can the extent of gene transfer with AAV4 and AAV5 be increased by delivery through minipumps? SPECIFIC AIM 4: Can AAV4 and AAV5 transduce cells in human brain tissue?